1. Field of the Invention
This invention relates to pyrido[2,3-b]indolizine derivatives and aza analogues thereof that selectively bind to corticotropin-releasing factor (CRF) receptors. It also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating stress related disorders such as post traumatic stress disorder (PTSD) as well as depression, headache and anxiety.
2. Description of the Related Art
Posselt, K., Arzneim.-Forsch. 1978, 28, 1056-65, describe the synthesis of 10-(4-methoxyphenyl)pyrido[2,3-b]indolizine. Volovenko et al., Khim. Geterotsikl. Soedin. 1991, 6, 852, describe the synthesis of 2-chloro and 2-methylthio-10-tosylmethylpyrimido[4,5-b]indolizine.
This invention provides novel compounds of Formula I which interact with CRF receptors.
In one aspect, the invention provides pharmaceutical compositions comprising compounds of Formula I. In another aspect, it provides compositions useful in treating stress related disorders such as post traumatic stress disorder (PTSD) as well as depression, headache and anxiety. These compositions include a compound of Formula I. Further, in a third aspect, the invention provides methods of treating such stress related disorders.
Accordingly, a broad aspect of the invention is directed to compounds of Formula I: 
Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, 4- or 5-pyrimidyl, each of which is optionally mono-, di-, or trisubstituted with halogen, trifluoromethyl, hydroxy, amino, mono- or di(C1-C6) alkyl amino, carboxamido, C1-C6 alkyl, C3-C7 cycloalkyl, or C1-C6 alkoxy, with the proviso that at least one of the positions ortho or para to the point of attachment of Ar to the tricyclic ring system is substituted;
R1 and R2 independently represent
C1-C6 alkyl;
C3-C7 cycloalkyl;
C3-C7 cycloalkyl(C1-C6)alkyl;
C1-C6 alkoxy(C1-C6)alkyl; or
aryl(C1-C6)alkyl where aryl is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2- or 3-thienyl or 2-, 4 or 5-pyrimidyl, each of which is optionally mono- or disubstituted with halogen, hydroxy, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, or (C1-C6 alkylene)xe2x80x94Axe2x80x94R4, wherein A is O, S, NH, or N(C1-C6 alkyl) and R4 is hydrogen, C3-C7 cycloalkyl, or C1-C6 alkyl; or
R1 and R2 taken together represent xe2x80x94(CH2)nxe2x80x94Axe2x80x94(CH2)mxe2x80x94 wherein n is 2, 3 or 4, A is methylene, oxygen, sulfur, or NR5, wherein R5 is hydrogen, C3-C7 cycloalkyl, or C1-C6 alkyl, and m is 0, 1, or 2;
R3 is C1-C6 alkyl, or (C1-C6 alkylene)xe2x80x94Gxe2x80x94R6, wherein G is O, S, NH, or N(C1-C6 alkyl) and R6 is hydrogen, C3-C7 cycloalkyl, or C1-C6 alkyl; and
W, X, Y, and Z are independently N or Cxe2x80x94R7, wherein R7 is hydrogen, C3-C7 cycloalkyl, or C1-C6 alkyl.
These compounds are highly selective partial agonists or antagonists at CRF receptors and are useful in the diagnosis and treatment of stress related disorders such as post traumatic stress disorder (PTSD) as well as depression and anxiety.
Another aspect of the invention is directed to intermediates useful in the preparation of the compounds of Formula I.
In a further aspect, the invention provides methods for making the compounds of Formula I and the intermediates for preparing such compounds.
Preferred compounds of Formula I are those where Ar is phenyl substituted in the 2, 4, and 6 positions, preferably with methyl, ethyl or propyl; naphthyl substituted in the 2 and 6 positions, preferably with methyl, ethyl or propyl; or 3-pyridyl substituted in the 2, 4, and 6 positions, preferably with methyl, ethyl or propyl; 5-pyrimidiyl substituted in the 2, 4, and 6 positions, preferably with methyl, ethyl, or propyl. Particularly, preferred components of Formula I include those where the Ar group is substituted in the 2 and 6 or the 2, 4, and 6 positions with methyl.
Preferred compounds of the invention have Formula II: 
wherein Ar, R1, R2, and R3 are as defined above for Formula I; and
X, Y, and Z are independently N or Cxe2x80x94R7, wherein R7 is hydrogen, C3-C7 cycloalkyl, or C1-C6 alkyl.
Preferred compounds of Formula II are those where X and Z are both CH and Y is CH or nitrogen. More preferred compounds of Formula II are those where R3 is C1-C4 alkyl or C3-C6 cycloalkyl(C1-C3)alkyl. Other more preferred compounds of Formula II are those where R1 and R2 independently represent C1-C6 alkyl, C3-C7 cycloalkyl(C1-C6)alkyl, xe2x80x94(CH2)2O(CH2)2xe2x80x94; and Ar is phenyl trisubstituted with C1-C3 alkyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the tricyclic ring system. Particularly preferred compounds of the Formula II are those where Ar is phenyl trisubstituted with methyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the tricyclic ring system.
Other particularly preferred compounds of Formula II are those where X, Y and Z are all CH.
Other preferred compounds of the invention have Formula III 
wherein Ar, R1, R2, and R3 are as defined above for Formula I; and
X and Z are independently N or Cxe2x80x94R7, wherein R7 is hydrogen, C3-C7 cycloalkyl, or C1-C6 alkyl
More preferred compounds of Formula III are those where R3 is C1-C4 alkyl or C3-C6 cycloalkyl(C1-C3)alkyl. Other more preferred compounds of Formula III are those where R1 and R2 independently represent C1-C6 alkyl, C3-C7 cycloalkyl(C1-C6)alkyl, xe2x80x94(CH2)2O(CH2)2xe2x80x94; and Ar is phenyl trisubstituted with C1-C3 alkyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the tricyclic ring system. Particularly preferred compounds of the Formula III are those where Ar is phenyl trisubstituted with methyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the tricyclic ring system.
Still other preferred compounds of the invention have formula: 
wherein
wherein Ar, R1, R2, and R3 are as defined above for Formula I; and
W, X, and Z are independently N or Cxe2x80x94R7, wherein R7 is hydrogen, C3-C7 cycloalkyl, or C1-C6 alkyl.
Preferred compounds of Formula IV are those where X and Z are both CH.
More preferred compounds of Formula IV are those where R3 is C1-C4 alkyl or C3-C6 cycloalkyl(C1-C3)alkyl. Other more preferred compounds of Formula IV are those where R1 and R2 independently represent C1-C6 alkyl, C3-C7 cycloalkyl(C1-C6)alkyl, xe2x80x94(CH2)2O(CH2)2xe2x80x94; and Ar is phenyl trisubstituted with C1-C3 alkyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the tricyclic ring system. Particularly preferred compounds of the Formula IV are those where Ar is phenyl trisubstituted with methyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the tricyclic ring system.
Other particularly preferred compounds of IV are those where W is CH and X and Z are both CH.
Yet other preferred compounds of the invention have formula: 
wherein Ar, R1, R2, and R3 are as defined above for Formula I; and
X and Z are independently N or Cxe2x80x94R7, wherein R7 is hydrogen, C3-C7 cycloalkyl, or C1-C6 alkyl.
Preferred compounds of Formula V are those where R3 is C1-C4 alkyl or C3-C6 cycloalkyl(C1-C3)alkyl. Other more preferred compounds of Formula V are those where R1 and R2 independently represent C1-C6 alkyl, C3-C7 cycloalkyl(C1-C6)alkyl, xe2x80x94(CH2)2O(CH2)2xe2x80x94; and Ar is phenyl trisubstituted with C1-C3 alkyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the tricyclic ring system. Particularly preferred compounds of the Formula V are those where Ar is phenyl trisubstituted with methyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the tricyclic ring system.
The invention also provides intermediates useful in preparing compounds of Formula I. These intermediates have Formulae VI-X. 
where Ar, and X, Y and Z are defined as above for Formula I.
Preferred compounds of Formula VI are those where Y is CH or N and X and Z are CH, and Ar is phenyl trisubstituted with C1-C3 alkyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the methylene group. Particularly preferred compounds of the Formula VII are those where Y is CH or N, X and Z are CH, and Ar is phenyl trisubstituted with methyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the methylene group. 
where R8 is NH2 or Nxe2x95x90C(R3)C(R7) where R3 and R7 are as defined above for Formula I; and
Ar, and X, Y and Z are defined as above for Formula I.
Preferred compounds of Formula VII are those where Y is CH or N and X and Z are CH, and Ar is phenyl trisubstituted with C1-C3 alkyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the bicyclic ring system. Particularly preferred compounds of the Formula VII are those where Y is CH or N; X and Z are CH; and Ar is phenyl trisubstituted with methyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the bicyclic ring system. 
where R9 is halogen or hydroxy; and R3, R7, Ar, and X, Y and Z are defined as above for Formula I.
Preferred compounds of Formula VIII are those where Y is CH or N; X and Z are CH; and Ar is phenyl trisubstituted with C1-C3 alkyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the tricyclic ring system. Particularly preferred compounds of the Formula VIII are those where Y is CH or N; X and Z are CH; and Ar is phenyl trisubstituted with methyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the tricyclic ring system. 
where R10 is NH2 or NHC(O)R3, where R3 is as defined above for Formula I; and Ar, and X, Y and Z are defined as above for Formula I.
Preferred compounds of Formula IX are those where Y is CH or N; X and Z are CH; and Ar is phenyl trisubstituted with C1-C3 alkyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the bicyclic ring system. Particularly preferred compounds of the Formula IX are those where Y is CH or N; X and Z are CH; and Ar is phenyl trisubstituted with methyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the bicyclic ring system. 
where R3, Ar, X, Y and Z are defined as above for Formula I.
Preferred compounds of Formula X are those where Y is CH or N; X and Z are CH; and Ar is phenyl trisubstituted with C1-C3 alkyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the tricyclic ring system. Particularly preferred compounds of the Formula X are those where Y is CH or N; X and Z are CH; and Ar is phenyl trisubstituted with methyl in the 2, 4, and 6 positions relative to the point of attachment of Ar to the tricyclic ring system.
In certain situations, the compounds of Formula I may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds in Table I and their pharmaceutically acceptable acid addition salts. In addition, if the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOCxe2x80x94(CH2)nxe2x80x94COOH where n is 0-4, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.
Where a compound exists in various tautomeric forms, the invention is not limited to any one of the specific tautomers. The invention includes all tautomeric forms of a compound.
By xe2x80x9cC1-C6 alkylxe2x80x9d or xe2x80x9clower alkylxe2x80x9d in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. Preferred C1-C6 alkyl groups are methyl, ethyl, propyl, butyl, cyclopropyl and cyclopropylmethyl.
By xe2x80x9cC1-C6 alkoxyxe2x80x9d or xe2x80x9clower alkoxyxe2x80x9d in the present invention is meant straight or branched chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
By the term xe2x80x9chalogenxe2x80x9d in the present invention is meant fluorine, bromine, chlorine, and iodine.
Representative pyrido[2,3-b]indolizine derivatives and their aza analogues of the present invention are shown in Table 1. The number below each compound is its compound number.
The interaction of compounds of the invention with CRF receptors is shown in the examples. This interaction results in the pharmacological activities of these compounds as illustrated in relevant animal models.
The compounds of general formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general formula I and a pharmaceutically acceptable carrier. One or more compounds of general formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monoleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monoleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of general formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compounds of general formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
The preparation of the pyrido[2,3-b]indolizines and aza analogues thereof of the present invention is illustrated in Schemes I and II. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention. 
In Scheme I, the variables Ar, R1, R2, R3, R7, X, Y, and Z are defined as above for Formula I. 
In Scheme I, the variables Ar, R1, R2, R3, X, Y, and Z are defined as above for Formula I.
The disclosures of all articles and references mentioned in in this application, including patents, are incorporated herein by reference.
The preparation of the compounds of the present invention is illustrated further by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures and compounds described in them.
Commercial reagents were used without further purification. DMSO refers to dimethyl sulfoxide. THF refers to tetrahydrofuran. DMF refers to dimethylformamide. Room temperature refers to 20xc2x0 to 25xc2x0 C. Concentration in vacuo implies the use of a rotary evaporator. Chromatography refers to flash column chromatography performed using 32-63 mm silica gel. Proton NMR chemical shifts are reported in parts per million (d) relative to tetramethylsilane as an internal standard.